A key challenge in the oral administration of biologics such as hormones, antibodies, growth factors, enzymes, and vaccines is overcoming the physiological barriers presented by the gastrointestinal tract. These include extreme pH environments, enzymatic degradation, and poor permeability across the intestinal epithelium. Encapsulation of biologics inside polymeric nanoparticles allows the therapeutic agent to be shielded from the low pH environment and enzymes of the GI tract. However, there are currently no strategies that efficiently and safely overcome the intestinal epithelium transport barrier. We propose to overcome this barrier by targeting biologic-encapsulated nanoparticles to the neonatal Fc receptor (FcRn) present in the intestines. The FcRn is responsible for active transport of IgG antibodies across the intestinal epithelium through the process of transcytosis. We hypothesize that using the Fc portion of IgG to target biologic-encapsulated nanoparticles to the FcRn will allow Fc-targeted nanoparticles to be actively transported across the intestinal epithelium and enter systemic circulation after oral administration. In this proposal, using insuli as a model biologic and diabetes as a model disease, we aim to develop insulin-encapsulated and FcRn-targeted nanoparticles for efficient oral delivery of insulin. Biodegradable and biocompatible polymers will be used to develop nanoparticles with sizes less than 100 nm that are able to encapsulate insulin with a load greater than 5%, release insulin with bioactivity greater than 90%, and are surface functionalized with IgG Fc fragments. The nanoparticles will be tested in an in vitro human epithelium cell model to demonstrate enhanced transcytosis due specifically to the FcRn and in vivo to evaluate the efficacy of insulin-encapsulated and FcRn-targeted nanoparticles after oral administration with a target bioavailability of 20% for insulin. Successful completion of this study will have a significant impact on the treatment of many diseases by overcoming a critical barrier and enabling efficient oral delivery of biologics.